Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease

BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related SCT.

The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic SCT (allo-HSCT). We applied whole-genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single-nucleotide polymorphisms (SNPs) in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong linkage disequilibrium between each other (R2 =0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P<0.00001 for BAT2 SNP rs11538264, and P<0.0001 for BAT3 SNP rs10484558), whereas the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs 2.6%, nominal P=1.15 × 10-8; and adjusted P=0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent a novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT

Do Daily Activities Impact Gas Tamponade - Retina Contact after Pars Plana Vitrectomy? A Computational Fluid Dynamics Study

Purpose:To calculate the retinal surface alternatively in contact with gas and aqueous because of fluid sloshing during daily activities such as ocular saccade, turning the head, standing up, and being a passenger of a braking car.Methods:Fluid dynamics of aqueous and gas tamponade was reproduced using computational methods using the OpenFOAM open-source library. The double-fluid dynamics was simulated by the volume of fluid method and setting the contact angle at the aqueous-gas-retina interface.Results:Sloshing increased the retinal surface in contact with aqueous by 13% to 16% regardless of fill rate and standing up determined the largest area of wet retina, followed by car braking, head rotation, and ocular saccade (P &lt; 0.001). All activities except the ocular saccade determined a significant increase in the surface of retina in contact with the aqueous (P &lt; 0.005). Car braking induced the highest shear stress (6.06 Pa); standing up determined the highest specific impulse and saccade the lowest.Conclusion:Daily activities instantaneously reduce the amount of retina consistently in contact with gas tamponade and increase shear stress giving aqueous a potential access to the subretinal space regardless of patients' compliance

Physical and Mental Fatigue Reduce Psychomotor Vigilance in Professional Football Players

Purpose: Professional football players experience both physical and mental fatigue (MF). The main aims of this randomized crossover study were to investigate the effect of MF on repeated-sprint ability (RSA) and the effects of both physical fatigue and MF on psychomotor vigilance. Methods: Seventeen male professional football players performed 10 maximal 20-m shuttle sprints interspaced by incomplete recovery (RSA test). Running speed, heart rate, brain oxygenation, and rating of perceived exertion were monitored during each sprint. The RSA test was preceded by either a 30-minute Stroop task to induce MF or by watching a documentary for 30 minutes (control [CON]) in a randomized counterbalanced order. Participants performed a psychomotor vigilance test at baseline, after the cognitive task (MF or CON), and after the RSA test. Results: Heart rate and rating of perceived exertion significantly increased, while running speed and brain oxygenation significantly decreased over the repeated sprints (P .001) with no significant differences between conditions. Response speed during the psychomotor vigilance test significantly declined after the Stroop task but not after CON (P = .001). Response speed during the psychomotor vigilance test declined after the RSA test in both conditions (P .001) and remained lower in the MF condition compared to CON (P = .012). Conclusions: MF does not reduce RSA. However, the results of this study suggest that physical fatigue and MF have negative and cumulative effects on psychomotor vigilance. Therefore, strategies to reduce both physical fatigue and MF should be implemented in professional football players

KSHV gB associated RGD interactions promote attachment of cells by inhibiting the potential migratory signals induced by the disintegrin-like domain

Background: Kaposi's sarcoma-associated herpesvirus (KSHV) glycoprotein B (gB) is not only expressed on the envelope of mature virions but also on the surfaces of cells undergoing lytic replication. Among herpesviruses, KSHV gB is the only glycoprotein known to possess the RGD (Arg-Gly-Asp) binding integrin domain critical to mediating cell attachment. Recent studies described gB to also possess a disintegrin-like domain (DLD) said to interact with non-RGD binding integrins. We wanted to decipher the roles of two individually distinct integrin binding domains (RGD versus DLD) within KSHV gB in regulating attachment of cells over cell migration

New Dihydrothiazole Benzensulfonamides: Looking for Selectivity toward Carbonic Anhydrase Isoforms I, II, IX, and XII

In the present study we investigated the structure-activity relationships of a new series of 4-[(3-ethyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides (EMAC10101a-m). All synthesized compounds, with the exception of compound EMAC10101k, preferentially inhibit off-target hCA II isoform. Within the series, compound EMAC10101d, bearing a 2,4-dichorophenyl substituent in position 4 of the dihydrothiazole ring, was the most potent and selective toward hCA II with an inhibitory activity in the low nanomolar range

Seeking Correlation Among Porin Permeabilities and Minimum Inhibitory Concentrations Through Machine Learning: A Promising Route to the Essential Molecular Descriptors

Developing effective antibiotics against Gram-negative bacteria remains challenging due to their protective outer membrane. With this study, we investigated the relationship between antibiotic permeation through the OmpF porin of Escherichia coli and antimicrobial efficacy. We measured the relative permeability coefficients (RPCs) through the bacterial porin by liposome swelling assays, including non-antibacterial molecules, and the minimum inhibitory concentrations (MICs) against E. coli. We developed a machine learning (ML) approach by combining classification and regression models to correlate these data sets. Our strategy allowed us to quantify the negative correlation between RPC and MIC values, clearly indicating that increased permeability through OmpF generally leads to improved antimicrobial activity. Moreover, the correlation was remarkable only for compounds with significant permeability coefficients. Conversely, when permeation ability is low, other factors play the most significant role in antimicrobial potency. Importantly, the proposed ML-based approach was set by exploiting the available seminal information from previous investigations in order to keep the number of molecular descriptors to the minimum for greater interpretability. This provided valuable insights into the complex interplay between different molecular properties in defining the overall outer membrane permeation and, consequently, the antimicrobial efficacy. From a practical perspective, the presented approach does not aim at identifying the “golden rule” for boosting antibiotic potency. The automated protocol presented here could be used to inspect, in silico, many alternatives of a given molecular structure, with the output being the list of the best candidates to be then synthesized and tested. This could be a valuable in silico tool for researchers in both academia and industry to rapidly evaluate novel potential compounds and reduce costs and time during the early drug discovery stage

Effects of caffeine on neuromuscular fatigue and performance during high-intensity cycling exercise in moderate hypoxia

Purpose: To investigate the effects of caffeine on performance, neuromuscular fatigue and perception of effort during high-intensity cycling exercise in moderate hypoxia. Methods: Seven adult male participants firstly underwent an incremental exercise test on a cycle ergometer in conditions of acute normobaric hypoxia (fraction inspired oxygen = 0.15) to establish peak power output (PPO). In the following two visits, they performed a time to exhaustion test (78 ± 3% PPO) in the same hypoxic conditions after caffeine ingestion (4 mg kg$^{−1}$) and one after placebo ingestion in a double-blind, randomized, counterbalanced cross-over design. Results: Caffeine significantly improved time to exhaustion by 12%. A significant decrease in subjective fatigue was found after caffeine consumption. Perception of effort and surface electromyographic signal amplitude of the vastus lateralis were lower and heart rate was higher in the caffeine condition when compared to placebo. However, caffeine did not reduce the peripheral and central fatigue induced by high-intensity cycling exercise in moderate hypoxia. Conclusion: The caffeine-induced improvement in time to exhaustion during high-intensity cycling exercise in moderate hypoxia seems to be mediated by a reduction in perception of effort, which occurs despite no reduction in neuromuscular fatigue

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

Selective inhibition of carbonic anhydrase IX and XII by coumarin and psoralen derivatives

A small library of coumarin and their psoralen analogues EMAC10157a-b-d-g and EMAC10160a-b-d-g has been designed and synthesised to investigate the effect of structural modifications on their inhibition ability and selectivity profile towards carbonic anhydrase isoforms I, II, IX, and XII. None of the new compounds exhibited activity towards hCA I and II isozymes. Conversely, both coumarin and psoralen derivatives were active against tumour associated isoforms IX and XII in the low micromolar or nanomolar range of concentration. These data further corroborate our previous findings on analogous derivatives, confirming that both coumarins and psoralens are interesting scaffolds for the design of isozyme selective hCA inhibitors